Alzheimer?s disease (AD) and related dementias (ADRD), for which no effective therapy exists, affect millions of people in the US and cost hundreds of billions of dollars in caregiving expenses. Health disparities in ADRD are a major unaddressed problem. Education and lifestyle contribute to this disproportion, but genetic factors may also be involved. Mitochondrial gene variations are often ignored from genomic analyses. Our group has developed a novel tool to study mitochondrial genetic variants, called Mitochondrial Genome Wide Association Study (MiWAS), and have already found several gene variants that increase risk for a variety of diseases. Furthermore, we have also validated a mitochondrial RNA Sequencing computational workflow in order to capture the mitochondrial transcriptome variations that contribute to disease. The MiWAS and mito- transcriptomic approaches are completely novel and innovative strategies to mine large databases for mtDNA and mito-ORF-RNA variations that could lead to the identification of novel ethnic-specific therapeutic targets for precision ADRD care. Moreover, we believe our proposed studies are highly significant, allowing for more precise identification of at risk individuals that can be targeted for early intervention or prevention. Our grant is thus paving the way to ethnic-specific stratification of ADRD risk reduction, e.g. with targeted personalized weight loss programs. Our analyses will be performed on two large longitudinal cohorts with well characterized cognitive phenotypes as well as genomic and transcriptomic data: HRS, and the REasons for Geographic And Racial Differences in Stroke cohort (REGARDS). Our central hypothesis is that certain ethnicities present differential ADRD risk because of mitochondrial genetic variants and mitochondrial transcriptome differences. For this grant, we assembled an interdisciplinary team to examine this hypothesis via these aims: 1: Identify ethnic-specific mitochondrial SNPs that predict cognitive decline and ADRD by employing MiWAS. 2: Determine whether mtSNPs interact with health disparities to predict cognitive decline over time and ADRD using innovative Mitochondria-Wide GxE Interaction Scan (MiWIS) approaches. We will study the interaction between mtSNPs and environmental factors in HRS that are related to socio-cultural exposures, to identify ethnic-specific mtSNPs that interact with health disparities. 3: Analyze ethnic-specific mito-transcriptomes of small open reading frames (sORFs) and identify differentially expressed MDP genes associated with cognitive decline and ADRD using novel mitochondrial-RNA capturing and bioinformatics approaches. Overall, we believe that this project will engage an interdisciplinary team of scientists that will provide a robust connection between ethnic-specific mtSNPS, mito-ORFs and ADRD. These compelling proposed analyses will help explain ethnic differences in ADRD risk and guide immediate diagnostic insights, targeted lifestyle interventions and novel therapeutic target identification.